Determinants of COVID-19 vaccine hesitancy among students and parents in Sentinel Schools Network of Catalonia, Spain

Vaccine hesitancy is defined as a delay in acceptance of vaccines despite its availability, caused by many determinants. Our study presents the key reasons, determinants and characteristics associated with COVID-19 vaccine acceptability among students over 16 years and parents of students under 16 years and describe the COVID-19 vaccination among students in the settings of sentinel schools of Catalonia, Spain. This is a cross-sectional study that includes 3,383 students and the parents between October 2021 and January 2022. We describe the student’s vaccination status and proceed a univariate and multivariate analysis using a Deletion Substitution Addition (DSA) machine learning algorithm. Vaccination against COVID-19 reached 70.8% in students under 16 years and 95.8% in students over 16 years at the end of the study project. The acceptability among unvaccinated students was 40.9% and 20.8% in October and January, respectively, and among parents was proportionally higher among students aged 5–11 (70.2%) in October and aged 3–4 (47.8%) in January. The key reason to not vaccinate themselves, or their children, were concern about side effects, insufficient research about the effect of the vaccine in children, rapid development of vaccines, necessity for more information and previous infection by SARS-CoV-2. Several variables were associated with refusal end hesitancy. For students, the main ones were risk perception and use of alternative therapies. For parents, the age of students, sociodemographic variables, socioeconomic impact related to the pandemic, and use of alternative therapies were more evident. Monitoring vaccine acceptance and refusal among children and their parents has been important to understand the interaction between different multilevel determinants and we hope it will be useful to improve public health strategies for future interventions in this population.

Introduction potential risks associated with vaccination against COVID-19 [19][20][21], immunization strategies against COVID-19 for children and adolescents must emphasize individual risks and benefits, recognizing for example, the emergence of more transmissible variants, such as Omicron [22,23]. There is a debate about the real benefit-risk of COVID-19 vaccines in children/adolescents, due to a lower susceptibility to infection or COVID-19 observed in this population when compared with adults, the recommendation to vaccinate everyone aged 12 and over against COVID-19 has established itself as a critical strategy to control the pandemic [21].
This study is part of the COVID-19 Sentinel Schools Network of Catalonia (CSSNC) project, whose main objective are to monitor actively SARS-CoV-2 infections and identify barriers and facilitators for SARS-CoV-2 prevention strategies in schools. The CSSNC also provides an active surveillance during the pandemic that gathered evidence for enhanced of health protocols to prevent the spread of SARS-CoV-2 and others respiratory virus in the school [24].
The objectives of this study are to describe the COVID-19 vaccine acceptance, intentions and the key reasons for hesitation and refusal among students over 16 years and parents of students under 16 years, in the CSSNC, during the academic year 2021-2022, as well as to identify potential multilevel determinants for these parameters.

Data collection
Data collection was carried out in two points of time, the first in October 2021 and the second in January 2022. We collected nominal data through an online questionnaire, but a paper version was provided when necessary, and the questionnaires were also available in Catalan, Spanish and English. Two survey models were developed, one for students under 16 years, and another for students over 16 years.
The questionnaire contained questions about socioeconomic and demographic characteristics, behavior, compliance with preventive measures, impacts of the pandemic and vaccination status, and was adapted from the COSMO study survey [25].
For unvaccinated participants we asked if they would accept to receive the COVID-19 vaccine in the following months, whose response options were accept, refuse and don't know. For those who expressed hesitancy and refusal intentions, we also asked about the reason.
The online questionnaire was prepared using REDCap, we shared it through a link with the school management team so that it could be sent to all students, parents or guardians and school staff. In addition, information panels were placed in schools, which included access to the survey via QR code. Before completing the survey, participants had to sign informed consent either in online or paper formats. In the second data collection, people who were already part of the project received the survey in their informed email.
The field team consisted of health professionals and researchers. Before starting the fieldwork, a series of sensitization meetings were held to inform the school community about the objectives of the study. In each school where participants were recruited, online and face-toface meetings were held about the study with the participation of the project team and the educational community (families, teachers and school staff).
All participants under 16 years were guided by their parents or guardians, who answered the questionnaire and signed the informed consent. Students over 16 years answered the questionnaire and signed the informed consent by themselves. For this reason, we present the outcomes for the following groups: students older than 16 years (vaccination status and intentions), students younger than 16 years (vaccination status) and parents of students younger than 16 years (vaccination intentions).

Outcomes and case definition
Our first outcome was vaccination status, as vaccinated, we considered those with at least one dose of COVID-19 vaccine and unvaccinated, individuals with no dose.
Regarding the vaccine intention, vaccine acceptance was used to describe a participant vaccinated with at least one dose of the COVID-19 vaccine or unvaccinated but with the intention of being vaccinated soon. We used vaccine hesitancy to describe unvaccinated participants, who were unsure whether they would be vaccinated and vaccine refusal to refers to all unvaccinated participants who expressed total refusal to be vaccinated.
Our second was outcome vaccine acceptability, defined as "Yes" if a participant was vaccinated with at least one dose of the COVID-19 vaccine or unvaccinated but with the intention of being vaccinated soon (vaccine acceptance) and as "No" for unvaccinated participants who were unsure whether they would be vaccinated (vaccine hesitancy) or unvaccinated participants who expressed total refusal to be vaccinated (vaccine refusal).

Independent variables
We investigated the association between characteristics and factors that could influence the intention of adolescents to get vaccinated and of parents to allow their children to be vaccinated against SARS-CoV-2. These factors were referred as independent variables including the following categories: sociodemographic, health, knowledge, attitudes and practices, measures to avoid a SARS-CoV-2 infection and COVID-19 related impacts. Each variable was categorized according to the question asked in the questionnaire (Table 1).

Statistical analysis
A descriptive approach was carried out to present the vaccination status for all students and acceptability and reasons for refusal and hesitancy for parents of students under 16 years and students over 16 years. To describe the frequency of these variables, we present the data collected in October 2021 and January 2022. For the analysis, the student's data were aggregated in two groups, under 16 years (3-15 years), and over 16 years due to different methodology of data collection.
Each variable had between 10 and 30% missing throughout the sample, resulting in missed observations, so prior to analysis, we performed an imputation of multiple data sets by the chained equation method, obtaining 20 imputed datasets [26], that allowed proceed univariate and multivariate analyzes with the same participants. We compared the values of imputed and unimputed variables using a chi-square test on the first set of imputed data, for each variable. We repeat the description presented in Tables 4 and 5, using the imputed dataset and, for univariate, we use the set of all imputed datasets. The univariate analysis was adjusted for a 3--15-year age group, using a binomial logistic regression, pooling the results through Rubin's Rules (RR). We calculated the Odds Ratio (OR) with 95% confidence interval (CI) and pvalue, which we considered p<0.05 statistically significant.
A multivariate analysis was performed only with the parents' database (students under 16 year) due to the low number of unvaccinated students over 16 years (n = 24). We tested multicollinearity with a correlation matrix for each variable, excluding those with a correlation coefficient greater than 0.8 in absolute value.
In the multivariate model we proceed a Deletion Substitution Addition (DSA), with 50 iterations. DSA is an algorithm for Machine Learning that chooses the model with the smallest Root Mean Square Error (RMSE). This method consists of adding, removing and replacing variables and performing a cross-validation in 5 rounds with 5 iterations, resampling the  Factual knowledge about COVID-19 (a) (b) low / high

Measures and behavior to avoid a SARS-CoV-2 infection
Adherence to vaccination strategies is important yes / no database in 5 random partitions where each model iterations is done in one partition and validated in the other 4, making that the model to be tested not only on the main sample but also on different subsamples. The DSA function was run in one imputed dataset, and a logistic regression was performed to all imputed datasets to keep only the significant variables, through a backward elimination. To ensure consistent results, the DSA model was used on the first and last imputed datasets, and on one more randomly selected dataset (dataset 11), and as a result, we obtained the same final model. The performance of the models was accessed by the Akaike Information Criterion (AIC), adjusted R-square, criteria that defined the choice for the DSA model. We performed a McNemar test, which selects participants who were matched in the two samples (N = 2,145), to see if there was significance between the difference in acceptability rates between October 2021 and January 2022 between parents and students.
All analyses were carried out with R (version 4.1.2). The imputation was proceeded by mice package and the Rubin's Rules by the pool function in the same package, in RStudio Software [27].

Ethics approval
This study was approved on 17 December 2020 by the Ethical Committee of the Foundation University Institute for Research in Primary Health Care Jordi Gol i Gurina (IDIAPJGol) (code 20/192-PCV). A written informed consent was obtained from school staff, and since it includes minors, was signed for parents or guardians of children under 16 years and by participants older than 16 years that signed by themselves. All documents were archived in a place accessed only by the researchers. The signed document provided information about, procedures, risks, use of the collected data, anonymity, confidentiality, and general information about the study. All participants were free to decline/withdraw consent at any time without providing a reason and without being subject to any resulting detriment.

COVID-19 vaccination status and intentions
The vaccination coverage against SARS-CoV-2 in CSSNC was 36.1% for students under 16 years and 92.4% for students over 16 years in October 2021, increasing to 70.8% and 95.8% <16y-old and >16y-old, respectively, in January 2022. Among unvaccinated students over 16 years 28 (30.1%) and 15 (62.5%), in October and January respectively, refused to be vaccinated. The acceptability among their parents was proportionally higher among students aged 5-11 in October (70.2%) and students aged 3-4 in January (47.8%) but considering the denominators this result must be interpreted with caution, the parents' intention also varied significantly between October 2021 and January 2022, according to the McNemar test (Table 2).

Reasons and determinants to hesitancy and refusal of COVID-19 vaccine
We investigated the reasons for hesitation or refusal among parents and students in this study. The 11 key reasons informed by parents in both endpoints, were quite similar, concerning about side effects (67.1% and 57.4% respectively); insufficient research about vaccine safety and efficacy in children (52.1% and 50.4% respectively) and demand for more information to deciding to vaccinate their children (53.5% and 34.5% respectively). For students, the key reasons to hesitancy or refusal were slightly different in the two periods. In October 2021 most unvaccinated students reported concern with the time to development the vaccine (63.6%), concern about side effects (50.9%) and necessity for more information before deciding to vaccinate (45.5%). In January 2022, the main reason was concerning about side effects (68.4%), time to development the vaccine (63.2%) and previous COVID-19 disease (42.1%) (Fig 1A and 1B).

Students' descriptive and univariate analysis
The perception that it is easy to avoid a SARS-CoV-2 infection (OR 0.29 95%CI 0.09-0.88) and the use of herbal supplements and homeopathies to avoid a SARS-CoV-2 infection (OR 0.22 95%CI 0.08-0.63) were negatively associated with vaccine acceptance. A higher self-perceived knowledge (OR 3.6 95%CI 1.27-10.11) were positively associated with acceptability. As expected, adherence to vaccination strategies overall (OR 15.23 95%CI 5. 13-45.19) and routine vaccination behavior (OR 5.49 95%CI 2.08-14.49) was strongly and positively associated with vaccine acceptability (Table 3).

Parents' descriptive, univariate and multivariate analysis
A negative association was found between COVID-19 vaccine acceptability and birthplace, when at least one of the parents was born outside Spain (OR 0.63 95%CI 0.46-0.86), houses with more than five people living together (OR 0.7 95%CI 0.49-0.99), decrease of family's economic situation during the pandemic (OR 0.65 95%CI 0.47-0.9), use of herbal supplement or homeopathy as a measure to prevent a SARS-CoV-2 infection (OR 0.44 95%CI 0.29-0.67), concern about spending too much time with family (OR 0.53 95%CI 0.29-0.97) ( Table 4).
In multivariate analyses, the variables associated with vaccine acceptability were age, adherence to previous vaccination, father work situation, influence of health care workers. Variables associated with refusal or hesitancy was use of herbal supplements and homeopathies ( Table 5).
The AIC for the DSA model was 1504.17 (SD = 11.47), mean of the 20 imputed data sets, and the adjusted mean R-square was 0.2 (SD = 0.006), which corresponds to the variability of the R-square obtained by the models of each of the imputed data sets, and suggests that similar results were obtained across all imputed datasets and may be an indicator of a high-quality imputation process.

Measures and behavior to avoid a SARS-CoV-2 infection
Adherence to vaccination strategies is important ��

Discussion
Our study found the COVID-19 vaccine acceptability was high among adolescents (96.7%) and parents (83.3%). The main reason to refusal and hesitancy reported by parents was concern about side effects, safety and lack of information, all variables associated. On the other hand, variables with impact in the vaccine acceptability were, students age, compliance of routine vaccination, work situation, use of alternative practices as homeopathy, perception about current health, and COVID-19 related impacts. The prevalence of COVID-19 vaccine hesitancy in Spain was estimated at 6.2%, the lowest according to a study with unvaccinated participants from eight Europeans countries, proceeded in June 2021, and the main determinants are gender, age, education and employment [11]. A meta-analysis estimates the prevalence of COVID-19 vaccine hesitancy at 25% globally, recommending interventions among women, people with low educational levels, unemployed, people living in households with five or more individuals, and those who no trust in the COVID-19 safety [5].
A review found a global average for COVID-19 vaccine acceptance of 61.4%, with significantly difference between countries, variating between 42.9% in Saudi Arabia and 91.4% in Brazil [17], while the overall Europe acceptance was 72.6% [11]. Another study found that in United States 49% of parents were agreeing to vaccinate their children and 44% are planning to vaccinate them when the vaccine become available [28]. In Saudi Arabia, 47.6% of parents were ready to vaccinate their children [29], in Turkey, 36% of parents were willing to their children receive the vaccine [30], however 66% of parents were hesitant about a foreign vaccine and 37.4% were hesitant with a domestic vaccine [31].
In this study, the highest rates of refusal of the COVID-19 vaccine were among parents of students aged 3 to 4 years (41-49%), however, at the time of the study, there was still no vaccine approved for this population. For the 5-11 group, the vaccine had been approved during the first round of data collection, and although we found 30-22% refusal, we also found a significant increase in vaccine coverage (0-63%) immediately after approval of the vaccine for this age group. Similar behavior in relation to vaccine refusal rates was observed [32], where besides the data collection about vaccination have been carried out in the recent approval

Measures and behavior to avoid a SARS-CoV-2 infection
Adherence to vaccination strategies is important �� context, the vaccination schedule was just starting, and the services were still organizing for this demand. The contradictory arguments about the risk-benefit and severity of infection in this age group probably also contributed to this hesitation. Finally, we found that parents or guardians of older children were more likely to allow their vaccination, a result similar was found in another study [23].
The main reason to refusal and hesitancy reported by parents was concern about side effects, safety and lack of information, all variables associated. Variables with impact in the vaccine acceptability were, students age, compliance of routine vaccination, work situation, use of alternative practices as homeopathy, perception about current health, and COVID-19 related impacts. Socioeconomic characteristics can be an obstacle to vaccination strategies, even considering the free vaccine [3,33], for example, in our study we found that being employed was associated with a higher probability of accepting the vaccination of their children, while a greater number of people living in the same household, a decrease in the family's economic situation during the pandemic was associated with a lower probability to vaccinate their children. Social determinants and characteristics related to less access to health policies and information had a greater impact on vaccine acceptability, a result also observed in different studies on coverage and acceptability among low-, middle-and high-income countries [4,34]. Moreover, it is known that the burden of COVID-19 has affected different socioeconomic groups with different intensity, as observed in this populational study about mortality associated with socioeconomic status in Barcelona, Spain [35].
The parents' migratory situation, when at least one was born abroad but lives in Spain, was associated with vaccine hesitancy, a similar result was founded in a Canadian study [18]. Disparities in vaccination rates among students of different ethnicities was also demonstrated previously [15].
As expected, parents who live with health professionals were more likely to vaccinate their children. This result reinforces the important role of health care professionals on vaccine promotion strategies. Vaccine hesitancy among health professionals, can be a very important problem to public health strategies and, in this case, for vaccine acceptance, since trust in public health authorities can be an important influence on the decision to vaccinate or vaccinate persons in their care [3,36], as well as the message that reinforces safety and efficacy, disseminated by health professionals when vaccinating, can be useful to minimize vaccine hesitancy and refusal [34]. Also, they are a high-risk group for exposure to SARS-CoV-2 and had an understandable role in the transmission of the virus, for this reason, HCW were a priority group eligible for vaccination as soon as possible [36,37].
Parents who had perceived their children are healthy were more likely to allow them to be vaccinated, the same result was observed in a study with health professionals [38]. The history of receiving previous vaccine for another diseases among parents and students had increases the likely to be vaccinated and allow vaccinated their children, also, parents and adolescents who were previous vaccinated had more likely to accept the COVID-19 vaccine, findings consistent with another previous studies [38][39][40][41][42][43].
Use of alternative medicines such as homeopathy, that had a negative association with vaccine acceptability among both, parents and adolescents. This can be related to the lower use of health services and distrust of pharmacological therapies by these users. In addition, personal beliefs were already associated with vaccine refusal among parents in previous studies [44]. A Spanish study found a lower demand for influenza vaccination among homeopathy users, that rejects the vaccine for themself and for their children [45]. Moreover, family uptake behavior, can affect vaccine uptake among adolescents, as indicated in previous studies [39].
For unvaccinated students, the main reasons to vaccine refusal or hesitancy were concern about side effects, safety and vaccine distrust, agreeing with other studies in similar populations that demonstrated the significance of these variables in the decision not to be vaccinated [40,41]. The associated variables among students were risk perception, knowledge, alternative medical practices as homeopathy and compliance of routine vaccination. Students with higher perceived knowledge about COVID-19 were more likely to accept the vaccine, that is coherent with the discussion about access to adequate health information as an important predictor to vaccine acceptability [46][47][48].
Students that belief is easy to avoid a SARS-COV-2 infection, that is, who do not perceive the risk to be infected were more likely to refuse the vaccine against COVID-19, consistent with other studies [40,49].
A previous SARS-CoV-2 infection as a reason for vaccine refusal or hesitation increased between October 2021 and January 2022 among the participants may be related with the large wave caused by the Omicron variant in Catalonia, occurred in early December 2021, between the two points of the study data collection. The higher transmissibility and increasing infections, in fully vaccinated people included, could be associated with untrust and doubts about the vaccine effectiveness increasing the hesitation. Moreover, unlike the beginning of the pandemic, the perception of risk has changed, and people believe that COVID-19 has become a mild disease now.
Vaccine access is an important goal for health policies. It is very important understand how the lack of information, personal beliefs, limited health literacy and lower risk awareness was associated with vaccine refusal and hesitancy as discussed by another research [40]. Previous study showed that recommendation for the Government has strongly associated with acceptance [48], and especially when qualified information is available [23,29,44,50,51].

Limitations
Although the study design was adequate for the purpose of the study, the results should be extrapolated with caution. Predictive capacity of the statistical models applied in this study are considerable high, but, despite the high prevalence of COVID-19 vaccine acceptability in our sample, the study population does not represent the overall children and parents of the country.
The sample heterogeneity allows to generate several hypotheses, these would eventually need to be confirmed with population-based surveys. The reported vaccine acceptability may not reflect actual vaccination behavior as well. The fact that vaccination intentions were only asked for those who were not yet vaccinated, have also reduced this population size over time. Therefore, new research, especially longitudinal studies at different intervals, will be needed to investigate and evaluate this behavior in different periods of COVID-19 vaccination strategies.

Conclusions
This is the first investigation into COVID-19 vaccine hesitancy among parents and adolescents in Catalonia, Spain. Precaution regarding parental vaccination of children is consistently present across different periods of the pandemic, suggesting that individual risk-benefit continues to guide decision-making processes regarding vaccination.
Findings on the impact of social and structural factors on COVID-19 vaccine acceptability highlight the importance of specifically targeted interventions to address frequent misunderstandings and reinforce the common benefit of vaccination at the population level.
The evolving nature of SARS-CoV-2 and the potential role of vaccines in the pediatric population are still full of uncertainties. Both understanding the biological evolution of the virus and the persistence of natural and acquired immune protection will be crucial in defining vaccine recommendations for children.
Finally, the emergency response to SARS-CoV-2 needs to leave us a legacy of a health system prepared for increasingly efficient responses to future threats to public health. In this context, monitoring compliance and evolution of preventive public health measures, such vaccine hesitancy has been important to better understand the interaction between different multilevel determinants and its maintenance over time will be necessary to correctly delineate future interventions.